Project Summary The objective of this proposal is to break the vicious cycle of obesity/metabolic dysfunction during pregnancy. Lifestyle interventions in obese women during pregnancy have had limited success in improving maternal or offspring short and long-term metabolic health. We propose that lifestyle interventions need to be initiated prior to conception in overweight and obese women (henceforth referred to as obese) in order to first improve maternal metabolism. Lifestyle interventions will take place in the Cleveland Community Recreation Centers. Metabolic evaluations will be conducted in the Clinical Research Units of the Case Western Reserve Clinical Translational Science Center (CTSC). This strategy will result in decreased fetal adiposity and improved metabolic function in the offspring. We plan to recruit 200 obese women to pursue the following specific aims: Specific Aim 1: To investigate the physiological significance of lifestyle intervention in preparation for pregnancy (LIPP) on maternal and neonatal metabolism and adiposity in humans. Specific Aim 1a. We hypothesize that preconception lifestyle intervention will facilitate lower maternal insulin resistance, inflammation, weight, adiposity, incretin response and energy expenditure compared to usual care. We will link these changes in maternal metabolism with fetal growth (SA1b). Specific Aim 1b. We hypothesize that in women initiating pre-pregnancy lifestyle intervention will deliver a baby with lower birth weight and fat accretion, insulin resistance, and inflammatory profile at birth. Body composition will be measured using anthropometrics and air displacement densitometry (Pea Pod). Specific Aim 2: To determine the molecular effects whereby lifestyle intervention initiated before pregnancy improves placental mitochondrial lipid oxidation and lipid accumulation. We hypothesize that lifestyle intervention before pregnancy will improve placental mitochondrial oxidation and decrease lipid esterification/storage. Isotope-labeled fatty acid oxidation and esterification will be quantified in vitro in placental explants from a subset of women. Mitochondrial lipid metabolism and content will be measured using qRT-PCR and Elisa. Placental lipids will be quantified by mass spectrophotometry and correlated with neonatal adiposity and maternal metabolism providing a mechanistic link to SA 1.